To continue systematic mapping for a predisposing locus to manic-depressive illness we have screened more than 150 marker loci on chromosomes 2, 7, 13, 15, 17, 20 and 22. This genetic distance span about one third of the entire human genome. Up to 20 affected pedigrees were examined. By two- point analysis most of these loci can be excluded. On marker loci where interesting positive lod scores on a subset of the pedigrees were obtained, two-point and multipoint heterogeneity tests were performed. No linkage to illness has been detected. By genetic linkage mapping in CEPH pedigrees, we have located the m4 human muscarinic receptor in a cluster with D11S149 and D11S436 close to the centromere of chromosome 11, human cannabinoid receptor near the chromosome 6 centromere, stefin A is flanked by D3S47 and D3S21 on chromosome 3, and cathespin B is linked to lipoprotein lipase (LPL) on chromosome 8. The human endothelin-1 gene (EDN1) was mapped to the tip of chromosome 6. Following our elucidation of the genomic organization of the human glucocorticoid receptor (hGR), we completed the sequencing of the CpG-rich island which flanks the gene. Multiple promoter elements and putative hormone responsive elements (HRE) were identified. We constructed a long range physical map of the region using probes derived from hGR cosmid clones by pulsed field gel electrophoresis (PFGE). Several CpG-rich islands were identified within an approximately 2000 kb region. Using this map we have determined that hGR is linked to two G protein-coupled receptors, beta 2 and alpha 1 adrenergic receptors (AR) (beta2 AR and alpha1 AR), within an approximately 1300 kb fragment. To establish the phylogenetic relationships between members of the steroid receptor superfamily we have constructed a phylogenetic tree and found three different clusters, with two of these divided into subclusters. Several "orphan receptors" form a major subcluster.